Current strategies aimed at combating methamphetamine (METH) abuse do not appear to be effective and it is likely that METH abuse will continue to increase in the future. This is a serious concern, because METH abuse is associated with several adverse cerebrovascular pathologies of which the blood-brain barrier (BBB) breakdown is an underlying component. Interestingly, METH users have decreased levels of antioxidant capacity, a condition that is known to be associated with neurotoxicity and impaired vascular functions. Exercise is a modifiable behavioral factor known to have numerous health promoting effects that are mediated in part by an increase in antioxidant protection. We propose that exercise can attenuate the cerebrovascular toxicity of METH at the level of the BBB via antioxidant related mechanisms. The central hypothesis of the present application is that exercise protects against METH-induced disruption of the BBB by enhancing the antioxidant capacity of cerebral microvessels and modulating the caveolae-associated signaling. Mechanistically, we will explore a link between exercise, METH-induced disruption of tight junction proteins, and alterations of caveolae-associated redox signaling in brain capillaries. Caveolae are the subset of lipid rafts that are characterized by the presence of caveolin proteins. The significance of METH-caveolae interaction is related to the fact that a variety of cell surface receptors and redox-regulated signaling pathways, including small GTPases such as the Ras and Rho cascades, are localized in caveolae. These pathways may participate in phosphorylation of tight junction proteins and thus regulate the integrity of the BBB. Importantly, our data indicate that exercise can modify METH-induced caveolae-associated signaling and regulate levels of caveolin-1 protein. These observations prompted us to propose that caveolae provide the signaling platform for cerebrovascular toxicity of METH that can be effectively targeted by exercise. Data arising from this proposal will be critical not only for a better understanding of the molecular mechanisms underlying METH-related cerebrovascular injury but will also contribute to better knowledge of how exercise can protect against vascular toxicity. The strength of our approach may lead to the discovery of novel drug targets used to combat METH abuse and/or related neurotoxicity. Furthermore, the results generated by the proposed research are likely to be relevant in other neurodegenerative diseases that have significant cerebrovascular components, such as stroke or Alzheimer's and Parkinson's diseases. We believe that the data obtained from this proposal will provide evidence that even moderate exercise can significantly contribute to brain regeneration in chronic cerebrovascular disorders. PUBLIC HEALTH RELEVANCE: Methamphetamine (METH) abuse results in a long-term impairment of vascular functions that remain compromised in abstinent METH users. Several toxic effects of METH, such as myocardial infarction, stroke, and cardiomyopathy, are directly related to vascular or cerebrovascular dysfunction. In addition, the disruption of the blood-brain barrier (BBB) has been established as one of the most prominent events of METH toxicity. We hypothesize that exercise can protect against METH-induced disruption of the BBB by enhancing the antioxidant capacity of cerebral microvessels and modulating the caveolae-associated signaling. Data arising from our proposal will be critical not only for a better understanding of the molecular mechanisms underlying METH-related cerebrovascular injury but also will contribute to better knowledge of how exercise can protect against vascular toxicity. The results generated by the proposed research are likely to be relevant to other neurodegenerative diseases that have significant cerebrovascular components, such as stroke or Alzheimer's and Parkinson's diseases. We believe that the data obtained from this proposal will provide evidence that even moderate exercise can significantly contribute to brain regeneration in chronic cerebrovascular disorders.